PROJECT SUMMARY More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States and the estimated annual economic burden of AUD is $249 billion. Approximately 88,000 Americans die from alcohol-related causes each year; untreated AUD is the fourth most preventable cause of death in the US. Four medications have been approved by the FDA to date for treating AUD, but none of these medications have proven to be effective across the heterogeneous groups of people with this disorder. Treating addiction more effectively has become a national priority and accelerating drug development for AUD is one of the priorities for NIAAA. The present proposal is intended to answer this call for accelerating drug development by exploring the potential of a novel anticonvulsant, lacosamide, as a candidate medication for the treatment of AUD. This drug, which is FDA-approved for the treatment of seizure disorders, has unique pharmacological actions that include enhancement of slow sodium channel inactivation and inhibition of collapsin response mediator protein-2 (CRMP-2). Alcohol consumption in mice that had knockdown of CRMP-2 within the nucleus accumbens was decreased from levels seen in control animals. In rodent studies, lacosamide administration has produced reductions in `excessive' drinking and has experimentally-induced decreased expression of the CRMP-2 protein. These findings implicate CRMP-2 as playing a role in the regulation of alcohol consumption. None of the FDA-approved AUD medications or medications commonly used off-label to treat AUD target this CRMP-2 pathway, making lacosamide a promising compound for AUD drug development. The aims of this study are to: 1) test the effects of lacosamide on alcohol self-administration and craving, 2) assess the effects of lacosamide on the reinforcing stimulant effects of a priming drink of alcohol, 3) test the effects of 5 days of lacosamide administration on cognitive function, and 4) test the effects of lacosamide on alcohol consumption and craving during a 5-day period of exposure. The effects of 5-days of lacosamide (300mg) or placebo will be evaluated in a human laboratory using an alcohol self-administration methodology. In this within-subjects crossover design, heavy drinkers (N=24) will be randomized to the order of exposure (lacosamide or placebo) prior to completing two alcohol self-administration trials. Subjects will receive a priming drink of alcohol and will have access to 8 alcoholic drinks over a 2-hour period. We anticipate that subjects will consume less alcohol during an alcohol self-administration trial when receiving lacosamide compared to when they are receiving placebo. Significant lacosamide-induced reductions in the quantity of alcohol self-administered will be considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II clinical studies testing lacosamide with a treatment-seeking AUD population. These results may also help to spur further pre-clinical investigation into the role played by CRMP-2 in regulating both alcohol consumption and alcohol seeking behaviors.